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Toxicity, Carbamazepine
Updated: Feb 13, 2008
Introduction
Background
Carbamazepine (Tegretol) has been used for treatment of trigeminal neuralgias since 1960. Since carbamazepine received approval for use as an antiepileptic agent in the United States in 1974, it became widely used for the management of partial or tonic-clonic epilepsy. Carbamazepine is also used as a treatment for patients with manic-depressive illness, postherpetic neuralgia, or phantom limb pain. Some of the available dosage forms for carbamazepine include 100- and 200-mg oral tablets and a 100-mg/5-mL oral suspension.The therapeutic plasma concentration is 4-12 mg/L. A peak plasma level is achieved in 6-24 hours. Controlled-release formulation could result in peak levels as late as 4 days after administration.1 The volume of distribution is 1-2 L/kg. Carbamazepine is approximately 75-80% protein bound, and approximately 2-3% is excreted unchanged in the urine. Carbamazepine is oxidized by hepatic microsomal enzymes to produce its active metabolite, carbamazepine 10,11-epoxide. The serum concentration of the epoxide metabolite is approximately 20% in children and 10-15% in adults.
Autoinduction of microsomal enzyme results in a shorter carbamazepine half-life (10-20 h) in patients who use the drug long-term compared with those with a short-term exposure (31-35 h). The autoinduction process takes about 4 weeks.
In terms of drug interactions, carbamazepine induces the metabolism of other anticonvulsant drugs such as phenytoin, clonazepam, primidone, valproic acid, and ethosuximide. Inhibitors of hepatic microsomal enzymes such as erythromycin, clarithromycin, cimetidine, and propoxyphene increase carbamazepine levels.
Pathophysiology
Carbamazepine is a complex drug that has both anticonvulsant properties in therapeutic doses and a proconvulsant property in overdose situations with supratherapeutic serum levels. Carbamazepine is chemically and stereospatially related to the tricyclic antidepressant (TCA) imipramine; it is spatially similar to phenytoin. The therapeutic anticonvulsant mechanism of carbamazepine is similar to phenytoin and is believed to be primarily related to the blockade of presynaptic voltage-gated sodium channels.
Blockage of sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. It also inhibits N -methyl-D-aspartate (NMDA) receptors and CNS adenosine receptors. Carbamazepine also has powerful anticholinergic properties through inhibition of the muscarinic and nicotinic acetylcholine receptors. The seizures are largely secondary to a central anticholinergic syndrome. The coma and respiratory depression associated with overdose may be related to sodium channel suppression of neurotransmission. Carbamazepine causes antagonism at the adenosine subtype A1 receptor and agonism at the adenosine subtype A2 receptor. In lower therapeutic doses, this may be partially responsible for the anticonvulsant effect, whereas, in overdose situations, it may increase sedation or precipitate coma.
Cardiac arrhythmias due to carbamazepine are related to the sodium channel effects and the anticholinergic effects. In therapeutic doses, the cardiovascular sodium channels are only minimally affected, and carbamazepine does not appear to be proarrhythmic. However, in overdose situations, carbamazepine produces sodium channel blockade effects similar to those of TCAs.
Frequency
United States
Because of widespread use of carbamazepine in patients with pediatric epilepsy, the incidence of carbamazepine poisoning is increasing in all age groups. In 1997, the American Association of Poison Control Centers recorded 7151 cases of carbamazepine intoxication.2
Mortality/Morbidity
- In 2004, among 4845 exposures to carbamazepine, 232 patients had a major outcome, and 4 deaths were reported.2
- Complications of severe poisoning include coma, respiratory depression, seizures, hypotension, and GI hypomotility.
- Cardiac toxicity is uncommon in children, especially in those who have a structurally normal heart.
Sex
- No specific sex predilection has been noted.
Age
- Of 4845 cases of carbamazepine toxicity reported by the American Association of Poison Control Centers in 2004, a total of 1157 involved persons younger than 6 years.2
- Most pediatric patients are younger than 6 years.
Clinical
History
- Ingestion history
- Accidental ingestions are common in children younger than 6 years; suicidal ingestions typically occur in adolescents.
- Other causes of carbamazepine poisoning include iatrogenic overdose; dosage errors; and interactions with drugs such as erythromycin, cimetidine, isoniazid, and propoxyphene. All these drugs increase the levels of carbamazepine by competitively inhibiting its metabolism.
- The medication source is usually the patient himself or herself or another family member who is taking carbamazepine for seizure control or the treatment of other illness.
- Symptom history
- Symptoms usually appear within 6 hours of ingestion but may be delayed as long as 24 hours after the ingestion. Case reports indicate the possibility of delayed absorption, which causes levels to peak as late as 72 hours.
- Mild ingestions cause vomiting, drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, and hallucinations.
- Severe intoxications may produce coma, seizures, respiratory depression, and hypotension.
Physical
Carbamazepine toxicity should be considered in any child who presents with seizures, apnea, or an unexplained change in mental status, particularly when the child has access to the drug. The serum concentration may not be correlated with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not the serum carbamazepine concentration.
- Vital signs
- Hypothermia may occur after an acute overdose and may last as long as 10 hours.
- Hyperthermia may occur as part of a neuroleptic malignant syndrome.
- Neurologic effects
- Common neurologic effects include ataxia, slurred speech, nystagmus, dystonia and other extrapyramidal movements, and various degrees of CNS depression. Seizures are common in children with an epileptic disorder.
- In severe cases, coma, status epilepticus, or isolated seizures may occur.
- Neuroleptic malignant syndrome and transient ophthalmoplegia are also associated with carbamazepine overdose.
- Syndrome of inappropriate antidiuretic hormone secretion has also been reported.
- Respiratory effects
- Respiratory depression or apnea that requires mechanical ventilation may be observed within first 24 hours of the patient's presentation.
- Pulmonary edema or aspiration pneumonia may occur.
- Cardiovascular effects
- Cardiovascular effects are rarely observed in children.
- Hypotension, bradycardia, and conduction disorders may occur in those with an abnormal myocardium or a preexisting conduction defect.
- GI and hepatic effects
- Anticholinergic effects include delayed gastric emptying and decreased intestinal motility.
- With acute carbamazepine toxicity, chemical pancreatitis without accompanying pain or abnormalities may be present.
- Hematologic effects
- Neutropenia, thrombocytopenia, and aplastic anemia may occur with therapeutic doses or chronic intoxication but not after an acute overdose. Carbamazepine has also been reported to have induced immunoglobulin deficiency in some cases in therapeutic doses;3 however, this has not been reported in acute intoxication.
- Thrombocytopenia or aplastic anemia can result in bleeding; however, this effect is never seen with acute poisoning.
- Fatalities: Death may result from apnea, status epilepticus,4 aspiration pneumonitis, severe hepatitis, or aplastic anemia.
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References
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Further Reading
Keywords
carbamazepine overdose, carbamazepine poisoning, acute carbamazepine poisoning, accidental carbamazepine poisoning, Tegretol, Tegretol overdose, Tegretol toxicity, Carbatrol, Epitol, trigeminal neuralgias, tonic-clonic epilepsy, partial epilepsy, manic depression, postherpetic neuralgia, phantom limb pain, respiratory depression, seizures, hypotension, GI hypomotility, hyperthermia, neuroleptic malignant syndrome, status epilepticus, transient ophthalmoplegia, chemical pancreatitis, neutropenia, thrombocytopenia, aplastic anemia, immunoglobulin deficiency, aspiration pneumonitis, severe hepatitis
